Breast and prostate cancers are the most frequently diagnosed malignancies in the United States. Generally these cancers cannot be curatively resected, except when detected early. Other non-surgical approaches, such as radiotherapy or chemotherapy, also affect normal cells and result in side effects that limit treatment. In addition, all treatments for recurrent or metastatic cancer are palliative. Consequently, development of novel systemic approaches to treat advanced, recurrent or metastatic cancer is needed. Immunotherapy may have great potential as a promising treatment for cancer patients because of its specificity and freedom from toxic effects of chemotherapies.
CD8+ cytotoxic T lymphocytes (CTLs) can recognize and specifically kill tumor cells expressing peptides from tumor-associated antigens presented by major histocompatibility complex (MHC) class I molecules. Therefore, most current cancer immunotherapy strategies focus on induction of CTLs that lyse tumor cells. Antigen-specific cancer immunotherapy often relies on identification of epitopes expressed by cancer cells that can be used as targets for CD8+ T cells. However, the natural CTL epitopes of cancers are not always optimal because the CTL repertoire against high-affinity epitopes is often tolerized (Gross et al., J. Clin. Invest. 113(3):425-433, 2004). Epitope enhancement, by means of modification of the amino acid sequence of epitopes, was developed to improve the efficacy of vaccines primarily through increasing affinity of peptide for MHC molecules (Berzofsky et al., Nat. Rev. Immunol. 1(3):209-219, 2001).
Discovering tumor-specific antigens is critical to the development of effective cancer immunotherapy. Recently, a novel tumor associated antigen, POTE, was identified from several kinds of human cancers (Bera et al., Proc. Natl. Acad. Sci. USA 99(26):16975-16980, 2002; Bera et al., Cancer Res. 66(1):52-56, 2006). This tumor antigen is called POTE because its expression was first identified in normal prostate, ovary, testis, and placenta tissues, as well as in prostate cancer. The POTE gene family was found dispersed among eight different chromosomes (2, 8, 13, 14, 15, 18, 21, and 22) with different mRNA length. Nevertheless, the POTE cDNA sequence among various chromosomes is highly homogeneous with the divergence less than 10%. Subsequent studies revealed that POTE genes were expressed not only in prostate cancer, but also in a wide variety of human malignancies, including breast, colon, lung, ovary and pancreas. There are distinct patterns of expression of POTE in normal tissues and cancers. Among the various cancers, the POTE paralogs on chromosome 2 (POTE-2γ) are the most frequently expressed.
Because POTE mRNA is detectable only in a limited number of normal human tissues (prostate and testis in the male, and ovary and placenta in the female), the POTE protein is considered as a member of the cancer-testis antigen family. Expression of cancer-testis antigens in the placenta or testis should not lead to T-cell activation because of the very low expression of MHC class I molecules in these tissues. Therefore, the POTE antigen is a potential target for the immunotherapy of cancers, including breast and prostate cancers.